Novel prodrugs for antimicrobial amidines

ABSTRACT

A methods of treating an infection comprises administering a therapeutically effective amount of a compound described by the Formula (I):  
                 
 
     wherein:  
     X may be O, S, or NR′ wherein R′ is H or loweralkyl;  
     R 1  and R 2  may be independently selected from the group consisting of H, loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl, hydroxyalkyl, aminoalkyl, and alkylaminoalkyl;  
     R 3  and R 4  are each independently selected from the group consisting of H, loweralkyl, halogen, oxyalkyl, oxyaryl, and oxyarylalkyl;  
     R 5  is represented by a formula selected from the group consisting of:  
                 
 
      wherein:  
     X 1 , X 2 , and X 3  are independently selected from O and S; and R 6  and R 7  are independently selected from the group consisting of loweralkyl, aryl, alkylaryl, oxyaryl, an ester-containing substituent, and oxyalkyl; or a pharmaceutically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The instant application claims priority to U.S. ProvisionalApplication Serial No. 60/142,826 filed Jul. 8, 1999, the disclosure ofwhich is incorporated herein in its entirety.

FIELD OF THE INVENTION

[0002] The invention generally relates to methods for treatinginfections.

BACKGROUND OF THE INVENTION

[0003] A microbial infection such as, for example, Pneumocystis cariniipneumonia (PCP), is believed to be one of the leading causes of death inpatients suffering from AIDS. Pentamidine [i.e.,1,5-bis(4-amidinophenoxy)pentane] has been used as a therapeutic agentfor the treatment of PCP by intravenous infusion and as a prophylacticagent by aerosol dosage. However, the use of this drug may bepotentially disadvantageous in that it might be toxic and contribute tohypotension, hypoglycemia, and cardiac arrhythmias experienced by thepatient taking pentamidine.

[0004] Recent efforts have focused on developing other compounds forpotentially treating PCP. A number of aromatic diamidines have displayedpotential anti-PCP activity as reported in Boykin D. W., et al., J. Med.Chem., 1995, pp. 912-916; Tidwell, R. R. et al., Antimicrob. AgentsChemother. 1993, 37, p. 1713; Lombardy, R. L. et al., J. Med. Chem.1996, 39, p. 1452; and Kumar, A. et al., J. Med. Chem., 1996, 31, p.767. Notwithstanding any advantages that these drugs may possess, theymay be potentially undesirable since the drugs often exhibit low oralbioavailability.

[0005] Chemical modification of drugs into prodrugs can potentiallyimprove physiochemical properties such as water solubility,lipophilicity, transport of drug to the site of action, and presystemicdegradation, thus improving oral bioavailability. See Bundgaard, H., InDesign of Prodrugs; Bundgaard, H.;Ed.; Elsevier: Amsterdam, TheNetherlands, 1985; pp. 1-92; and Bundgaard, H., In A Textbook of DrugDesign and Development, Krogsgaard-Larsen, P.; Bundgaard, H.; Ed.;Harwood Academic Publ. Switzerland, 1991, pp. 113-191. A number ofreports exist on the prodrug modification of carboxyl, hydroxyl, thiols,and amino compounds. See, for example, Friis, G. J., et al., In ATextbook of Drug Design and Development, 2^(nd) Ed., Krogsgaard-Larsen,P., Liljefors, T. Madsen, U.; Ed.; Overseas Pub: Amsterdam, TheNetherlands, 1996, pp. 351-385; Digenis, G. A., et al., Druglatentiation, Handbook of Experimental Pharmacology, 1975, 28, pp.86-112. Moreover, Weller et al. (J. Med. Chem., 1996, 39, pp. 3139-3146)propose employing amidoximes and carbamate derivatives of mono-amidinesas prodrugs in order to potentially provide improved oral availabilityfor fibrogen antagonists. In addition, Boykin, D. W., et al., (Bioorg.Med. Chem. Lett., 1996, 6, pp. 3017-3020) have reported thatbis-amidoxime and O-methylamidoxime may be effective anti-PCP agents onboth oral and intravenous administration. U.S. Pat. No. 5,723,495 toHall et al. proposes administering a bis-benzamidoxime to a patient fortreating Pneumocystis carinii.

[0006] Notwithstanding the above efforts, there remains a need in theart to provide drugs that display improved activity.

SUMMARY OF THE INVENTION

[0007] A method of combating an infection to a subject in need of such atreatment is disclosed. The method comprises administering to thesubject a compound of the formula (I):

[0008] wherein:

[0009] X may be O, S, or NR′ wherein R′ is H or loweralkyl;

[0010] R₁ and R₂ may be independently selected from the group consistingof H, loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl, hydroxyalkyl,aminoalkyl, and alkylaminoalkyl;

[0011] R₃ and R₄ are each independently selected from the groupconsisting of H, loweralkyl, halogen, oxyalkyl, oxyaryl, andoxyarylalkyl;

[0012] R₅ is represented by a formula selected from the group consistingof:

[0013]  wherein:

[0014] X₁, X₂, and X₃ are independently selected from O and S; and

[0015] R₆ and R₇ are independently selected from the group consisting ofloweralkyl, aryl, alkylaryl, oxyaryl, an ester-containing substituent,and oxyalkyl;

[0016] or a pharmaceutically acceptable salt thereof, and wherein saidcompound of Formula (I) is administered in an amount to treat theinfection.

[0017] Preferably, R₆ and R₇ are independently selected from the groupconsisting of:

CH₃, CH₂CCl₃, CH₂CH₃,

[0018]

[0019] In one preferred embodiment, each of the substituents present onthe compound of formula (I) represented by the formula:

[0020] are present on the para positions of the aromatic groups onformula (I), although these substituents may be present in the metapositions.

[0021] The invention also discloses pharmaceutical compounds representedby the formula (I) described herein and pharmaceutically acceptablesalts thereof, as well as pharmaceutical formulations comprising thepharmaceutical compounds of formula (l) and pharmaceutically acceptablecarriers.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022]FIG. 1 illustrates a reaction in the synthesis of carbamates from2,5-bis(4-amidinophenyl)furan.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The present invention now will be described more fullyhereinafter with reference to the accompanying specification andexamples, in which preferred embodiments of the invention are shown.This invention may, however, be embodied in many different forms andshould not be construed as limited to the embodiments set forth herein.Rather, these embodiments are provided so that this disclosure will bethorough and complete, and will fully convey the scope of the inventionto those skilled in the art.

[0024] As used herein, the term “lower alkyl” refers to C1 to C4 linearor branched alkyl, such as methyl, ethyl, propyl, butyl, isopropyl,sec-butyl, and tert-butyl. The term “halogen” has its conventionalmeaning and refers to fluorine, chlorine, bromine, and iodine. The term“cycloalkyl” as used herein refers to C3 to C6 cyclic alkyl, such ascyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term “aryl” asused herein refers to C3 to C10 cyclic aromatic groups such as phenyl,naphthyl, and the like, and includes substituted aryl groups such as,but not limited to, tolyl. The term “hydroxyalkyl” as used herein refersto C1 to C4 linear or branched hydroxy-substituted alkyl, i.e., —CH₂OH,—(CH₂)₂OH, etc. The term “aminoalkyl” as used herein refers to C1 to C4linear or branched amino-substituted alkyl, wherein the term “amino”refers to the group NR′R″, wherein R′ and R″ are independently selectedfrom H or lower alkyl as defined above, i.e., —NH₂, —NHCH₃, —N(CH₃)₂,etc. The term “oxyalkyl” as used herein refers to C1 to C4oxygen-substituted alkyl, i.e., —OCH₃, and the term “oxyaryl” as usedherein refers to C3 to C10 oxygen-substituted cyclic aromatic groups.The term “alkoxyalkyl” as used herein refers to C1 to C4 linear orbranched alkoxy, such as methoxy, ethoxy, propyloxy, butyloxy,isopropyloxy, and t-butyloxy. The term “ester-containing substituent”refers to a substituent that may be directed linked to the compound offormula (I) via the single bond that is present directly off of theoxygen atom contained in the ester group or may be of the formula:

[0025] wherein R′ and R″ may be the same or different and can besubstituted or unsubstituted alkyl that may be saturated or unsaturated.It should be appreciated that the various groups referred to above maybe substituted or unsubstituted with various functional groups known toone skilled in the art.

[0026] As noted above, the methods of the present invention are usefulfor treating microbial infections such as P. carinii and Giardialamblia. The compounds may also be useful in treating fungal infectionssuch as Candida albicans, Cryptococcus neoformans, Aspergillusfumigatus, Fusarium solani, and combinations thereof. The methods of theinvention are useful for treating these conditions in that they inhibitthe onset, growth, or spread of the condition, cause regression of thecondition, cure the condition, or otherwise improve the generalwell-being of a subject afflicted with, or at risk of contracting thecondition.

[0027] Subjects to be treated by the methods of the present inventionare typically human subjects, although the methods of the presentinvention may be useful with any suitable subject known to those skilledin the art.

[0028] As noted above, the present invention provides pharmaceuticalformulations comprising the aforementioned active compounds, orpharmaceutically acceptable salts thereof, in pharmaceuticallyacceptable carriers for oral, intravenous, or aerosol administration asdiscussed in greater detail below. Also, the present invention providessuch compounds or salts thereof which have been lyophilized and whichmay be reconstituted to form pharmaceutically acceptable formulationsfor administration, as by intravenous or intramuscular injection.

[0029] The therapeutically effective dosage of any specific compound,the use of which is in the scope of present invention, will varysomewhat from compound to compound, and patient to patient, and willdepend upon the condition of the patient and the route of delivery. As ageneral proposition, a dosage from about 0.1 to about 50 mg/kg will havetherapeutic efficacy, with all weights being calculated based upon theweight of the active compound, including the cases where a salt isemployed. Toxicity concerns at the higher level may restrict intravenousdosages to a lower level such as up to about 10 mg/kg, with all weightsbeing calculated based upon the weight of the active base, including thecases where a salt is employed. A dosage from about 10 mg/kg to about 50mg/kg may be employed for oral administration. Typically, a dosage fromabout 0.5 mg/kg to 5 mg/kg may be employed for intramuscular injection.Preferred dosages are 1 μmol/kg to 50 μmol/kg, and more preferably 22μmol/kg and 33 μmol/kg of the compound for intravenous or oraladministration. The duration of the treatment is usually once per dayfor a period of two to three weeks or until the condition is essentiallycontrolled. Lower doses given less frequently can be usedprophylactically to prevent or reduce the incidence of recurrence of theinfection.

[0030] In accordance with the present method, pharmaceutically activecompounds as described herein, or pharmaceutically acceptable saltsthereof, may be administered orally as a solid or as a liquid, or may beadministered intramuscularly or intravenously as a solution, suspension,or emulsion. Alternatively, the compounds or salts may also beadministered by inhalation, intravenously or intramuscularly as aliposomal suspension. When administered through inhalation the activecompound or salt should be in the form of a plurality of solid particlesor droplets having a particle size from about 0.5 to about 5 microns,and preferably from about 1 to about 2 microns.

[0031] The present invention also provides a pharmaceutical compositionsuitable for intravenous or intramuscular injection. The pharmaceuticalcomposition comprises a compound of formula (I) described herein, or apharmaceutically acceptable salt thereof, in any pharmaceuticallyacceptable carrier. If a solution is desired, water is the carrier ofchoice with respect to water-soluble compounds or salts. With respect tothe water-insoluble compounds or salts, an organic vehicle, such asglycerol, propylene glycol, polyethylene glycol, or mixtures thereof,may be suitable. In the latter instance, the organic vehicle may containa substantial amount of water. The solution in either instance may thenbe sterilized in a suitable manner known to those in the art, andtypically by filtration through a 0.22 micron filter. Subsequent tosterilization, the solution may be dispensed into appropriatereceptacles, such as depyrogenated glass vials. Of course, thedispensing is preferably be done by an aseptic method, Sterilizedclosures may then be placed on the vials and, if desired, the vialcontents may be lyophilized.

[0032] In addition to compounds of formula (I) or their salts, thepharmaceutical compositions may contain other additives, such aspH-adjusting additives. In particular, useful pH-adjusting agentsinclude acids, such as hydrochloric acid, bases or buffers, such assodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodiumborate, or sodium gluconate. Further, the compositions may containmicrobial preservatives. Useful microbial preservatives includemethylparaben, propylparaben, and benzyl alcohol. The microbialpreservative is typically employed when the formulation is placed in avial designed for multidose use. Of course, as indicated, thepharmaceutical compositions of the present invention may be lyophilizedusing techniques well known in the art.

[0033] In yet another aspect of the present invention, there is providedan injectable, stable, sterile composition comprising a compound ofFormula (I), or a salt thereof, in a unit dosage form in a sealedcontainer. The compound or salt is provided in the form of alyophilizate which is capable of being reconstituted with a suitablepharmaceutically acceptable carrier to form a liquid compositionsuitable for injection thereof into a subject. The unit dosage formtypically comprises from about 10 mg to about 10 grams of the compoundor salt. When the compound or salt is substantially water-insoluble, asufficient amount of emulsifying agent which is physiologicallyacceptable may be employed in sufficient quantity to emulsify thecompound or salt in an aqueous carrier. One such useful emulsifyingagent is phosphatidyl choline.

[0034] Other pharmaceutical compositions may be prepared from thewater-insoluble compounds disclosed herein, or salts thereof, such asaqueous base emulsions. In such an instance, the composition willcontain a sufficient amount of pharmaceutically acceptable emulsifyingagent to emulsify the desired amount of the compound or salt thereof.Particularly useful emulsifying agents include phosphatidyl cholines,and lecithin.

[0035] Further, the present invention provides liposomal formulations ofthe compounds disclosed herein and salts thereof. The technology forforming liposomal suspensions is well known in the art. When thecompound or salt thereof is an aqueous-soluble salt, using conventionalliposome technology, the same may be incorporated into lipid vesicles.In such an instance, due to the water solubility of the compound orsalt, the compound or salt will be substantially entrained within thehydrophilic center or core of the liposomes. The lipid layer employedmay be of any conventional composition and may either containcholesterol or may be cholesterol-free. When the compound or salt ofinterest is water-insoluble, again employing conventional liposomeformation technology, the salt may be substantially entrained within thehydrophobic lipid bilayer which forms the structure of the liposome. Ineither instance, the liposomes which are produced may be reduced insize, as through the use of standard sonication and homogenizationtechniques.

[0036] Of course, the liposomal formulations containing the compoundsdisclosed herein or salts thereof, may be lyophilized to produce alyophilizate which may be reconstituted with a pharmaceuticallyacceptable carrier, such as water, to regenerate a liposomal suspension.

[0037] Pharmaceutical formulations are also provided which are suitablefor administration as an aerosol, by inhalation. These formulationscomprise a solution or suspension of a desired compound described hereinor a salt thereof, or a plurality of solid particles of the compound orsalt. The desired formulation may be placed in a small chamber andnebulized. Nebulization may be accomplished by compressed air or byultrasonic energy to form a plurality of liquid droplets or solidparticles comprising the compounds or salts. The liquid droplets orsolid particles should have a particle size in the range of about 0.5 toabout 10 microns, more preferably from about 0.5 to about 5 microns. Thesolid particles can be obtained by processing the solid compound or asalt thereof, in any appropriate manner known in the art, such as bymicronization. Most preferably, the size of the solid particles ordroplets will be from about 1 to about 2 microns. In this respect,commercial nebulizers are available to achieve this purpose. Thecompounds may be administered via an aerosol suspension of respirableparticles in a manner set forth in U.S. Pat. No. 5,628,984, thedisclosure of which is incorporated herein by reference in its entirety.

[0038] Preferably, when the pharmaceutical formulation suitable foradministration as an aerosol is in the form of a liquid, the formulationwill comprise a water-soluble compound or a salt thereof, in a carrierwhich comprises water. A surfactant may be present which lowers thesurface tension of the formulation sufficiently to result in theformation of droplets within the desired size range when subjected tonebulization.

[0039] As indicated, the present invention provides both water-solubleand water-insoluble compounds and salts thereof. As used in the presentspecification, the term “water-soluble” is meant to define anycomposition which is soluble in water in an amount of about 50 mg/mL, orgreater. Also, as used in the present specification, the term“water-insoluble” is meant to define any composition which hassolubility in water of less than about 20 mg/mL. For certainapplications, water soluble compounds or salts may be desirable whereasfor other applications water-insoluble compounds or salts likewise maybe desirable.

[0040] In another aspect, the invention relates to a process for makinga pharmaceutically active bis-aryl carbamate represented by formula (I).The process comprises reacting an aryl carbonate with bis-amidine in thepresence of an organic solvent to form the bis-aryl carbamate.

[0041] In one embodiment, the aryl carbonate may be represented by theformula:

[0042] wherein:

[0043] R is represented by:

[0044] wherein X is selected from the group consisting of H, N₂, F, andOCH₃; and

[0045] wherein R′ is selected from the group consisting of CH₃, CH₃OH₂,CH₂CCl₃, CH(OAc)CH₂, CH₂C₆H₅, and

[0046] wherein X is selected from the group consisting of H, NO₂, F, andOCH₃.

[0047] The aryl carbonate may be a symmetrical aryl carbonate. Specificexamples of aryl carbonates include, but are not limited to, diphenylcarbonate, bis(4-fluorophenyl)carbonate, bis(4-methoxyphenyl)carbonate,benzyl-4-nitrophenylcarbonate, 4-nitrophenyl thioethyl carbonate, and4-nitrophenyl-2,2,2-trichloroethyl carbonate, methyl 4-nitrophenylcarbonate, bis (3-fluorophenyl) carbonate, ethyl 4-nitrophenylcarbonate, (4-methyl-2-oxo-1,3-dioxol-4-en-5-yl)methyl 4-nitrophenylcarbonate, and 1-acetoxyethyl 4-nitrophenyl carbonate.

[0048] Examples of the pharmaceutically active bis-aryl carbamate thatmay be formed by the process of the invention include, but are notlimited to,2,5-bis[4-(N-2,2,2-trichloroethoxycarbonyl)amidinophenyl]furan,2,5-bis[4-(N-thioethylcarbonyl)amidinophenyl]furan,2,5-bis[4-(N-benzyloxycarbonyl)amidinophenyl]furan,2,5-bis[4-(N-phenoxycarbonyl)amidinophenyl]furan,2,5-bis[4-(N-(4-fluoro)phenoxycarbonyl)amidinophenyl]furan,2,5-bis[4-(N-(4-methoxy)phenoxycarbonyl)amidinophenyl]furan,2,5-bis[4(1-acetoxyethoxycarbonyl)amidinophenyl]furan, and 2,5-bis[4-(N-(3-fluoro)phenoxycarbonyl) amidinophenyl] furan.

[0049] Preferred organic solvents that may be employed in the process ofthe invention include, but are not limited to, dimethyl formamide,tetrahydrofuran/CH₃CN, and dioxane. Typically, tetrahydrofuran/CH₃CN isemployed in the presence of a base such as, but not limited to,diisopropylethylamine and triethylamine.

[0050] In addition to the above, the compounds described herein may beformed by various methods such as, for example, those described inWeller, T., et al., J. Med. Chem. 1996, 39, 3139-3146. Such a methodtypically relates to preparing a carbamate from amines of amidinesinvolving the reaction of the base with an appropriate chloroformate inthe presence of a base, typically aqueous sodium hydroxide orsodium/potassium bicarbonate. Nonetheless, since this method may sufferfrom potential drawbacks, an alternative method is disclosed herein forpreparing carbamates from amidines by reaction with carbonates, and inparticular aryl-alkyl and aryl-aryl carbonates. Traditionally carbonateshave been prepared by the reaction of tertiary amines andchloroformates. See Olofson, R. A., et al., J. Org. Chem. 1984, 49, pp.2081-2082; and Olofson, R. A. Pure and Appl, Chem. 1988, 60, pp.1715-1724. Additionally, the dealkylation of tertiary aliphatic amineswith phenyl chlorothionoformate has been reported in Millan D. S., etal., Tetrahedron Lett. 1998, 39, pp. 4387-4390.

[0051] A method for preparing carbonates is disclosed herein in whichpyridine is used as a base. As an example of the method, the4-nitrophenylalkyl carbonates described herein were prepared by reacting4-nitrophenol with the corresponding alkyl or arylchloroformates inmethylene chloride (CH₂Cl₂) using pyridine as a base,(1-acetyloxy)ethyl-4-nitrophenyl carbonate was prepared from1-chloroethyl-4-nitrophenyl carbonate according to published procedures.See Alexander, J. et al., J. Med. Chem., 1991, 34, pp. 78-81; and Lin,Y. I., et al., Bioorg. Med. Chem. Lett., 1997, 7, pp. 1811-1816.Symmetrical carbonates (i.e., diphenyl and bis(4-fluoro)- andbis(4-methoxy)phenylcarbonates described as 20-22) were synthesized byreacting phenol, 4-fluorophenol, and 4-methoxyphenol with phenyl,4-fluorophenyl, and 4-methoxypehnyl chloroformates respectively in apyridine/CH₂Cl₂ medium. 4-nitrophenyl(5-methyl-2-oxo-1,3-dioxo-4-ene-1-yl) methyl carbonate (23) wassynthesized from commercially available 4,5-dimethyl-1,3-dioxol-2-one bya four-step process as outlined in Sakamoto, F. et al., Chem. Pharm.Bull., 1984, 32, pp. 2241-2248. A modification to this procedure hasbeen proposed in the bromination step which ultimately leads to thecarbonate 23. The bromination of dimethyl dioxolone withN-bromosuccinimide in carbon tetrachloride in the presence ofα,α-azoisobutyronitrile as a free radical initiator under refluxconditions for 16 hours can afford the monobromide as a major product(90 percent) and dibromide as a minor product (10 percent). Displacementof the bromide by formate followed by acid catalyzed hydrolysis to givehydroxymethyl derivative was carried out according to a modification ofa procedure described in Alpegiani, M. et al., Synth. Commun., 1992, 22,pp. 1277-1282.

[0052] The synthesis of carbamates from amines is well known. Theinvention provides for the synthesis of carbamates of aromatic amidines.Methyl carbamate 2 was synthesized by the known method of reactingbis-amidine 1 with methylchloroformate in CH₂Cl₂ employing sodiumhydroxide as a base, often obtaining yields less than 50 percent. Analternative approach to potentially improve the yield and purity of thecarbamate involves reacting bis-amidine 1 with methyl-4-nitrophenylcarbonate in DMF to obtain methyl carbamate 2 at a yield of 80 percent.Carbamates 3-10 set forth in Table 1 were synthesized from bis-amidine 1and the appropriate carbonates in DMF or THF/CH₃CN (see Scheme 1). Abase was not employed when using DMF. A base (e.g.,diisopropylethylamine) was used when employing THF/CH₃CN. Symmetricalcarbonates were reacted with bis-amidine 1 to obtain the expectedcarbamates (7-9).

[0053] Table 1 contains the results of evaluation of the carbamate andcarbamate prodrugs 2-11 against P. carinii pneumonia in animmunosuppressed rat model (see S. K. Jones et at., Antimicrob. AgentsChemother. 1990, 34, pp. 1026-1030). Most of the prodrugs 2-11 appear tobe metabolized in vivo and were generally effective against PCP, orallyand intraveneously.

EXAMPLES

[0054] The invention will now be described in greater detail withreference to the following examples. It should be noted that theseexamples are for illustrative purposes only, and are not meant to limitthe invention.

Examples 1-25 Experimental Procedure

[0055] In the examples which follow, melting points were recorded usinga Thomas-Hoover (Uni-Melt) capillary melting point apparatus and wereuncorrected. TLC analysis was carried out on silica gel 60 F₂₅₄pre-coated aluminum sheets (0.20 mm layer thickness) (E. Merck ofWhitehouse Station, N.J.) and detected under UV light. IR spectra wererecorded using Perkin-Elmer Model 337 spectrometer sold by Perkin-Elmerof Norwalk, Conn. ¹H and ¹³C NMR spectra were recorded employing aVarian GX400 or a Varian Unityplus 300 spectrometer (both sold by Varianof Palo Alto, Calif.) and chemical shifts (5) are in ppm relative to TMSas internal standard. Mass Spectra were recorded on a VG Analytical70-SE spectrometer (Georgia Institute of Technology, Atlanta, Ga.). IRspectra were recorded using a Perkin-Elmer 2000 instrument. Elementalanalyses were obtained from Atlantic Microlab Inc. of Norcross, Ga. andare believed to be within 0.4 percent of the theoretical values unlessotherwise mentioned. All chloroformates were purchased from AldrichChemical Co. of St. Louis, Mo. Other chemicals and solvents werepurchased from either Aldrich or Fischer Scientific of Houston, Tex.4,5-Dimethyl-1,3-dioxol-2-one was purchased from TCI America Inc.2,5-Bis(4-cyanophenyl)furan, 2,5-bis(4-amidinophenyl)furan, and2,5-bis[4-(N-hydroxy)amidinophenyl]furan were synthesized as previouslydescribed. See Baijic, M., et al., Heterocycl. Commun., 1996, 2, pp.135-140; Das, B. P., J. Med. Chem. 1977, 20, pp. 531-536; and Boykin, D.W., et al., Bioorg. Med. Chem Lett., 1996, 6, pp. 3017-3020.Anti-Pneumocystis carinii pneumonia activity screening was carried outaccording to published methods. See Jones, S. K. et al., Antimicrob.Agents Chemother., 1990, 34, pp. 1026-1030; Hall, J. E., et al.,Antimicrob. Agents Chemother., 1998, 42, pp. 666-674; and Tidwell, R.R., et al., J. Med. Chem., 1990, 33, pp. 1252-1257. Compounds wereroutinely tested orally at 33 μmol/kg/day and intravenously at 22μmol/kg/day. Saline- and pentamidine treated groups of rats wereincluded as negative and positive controls, respectively.

[0056] Bold numbers that are listed in connection with each examplecorrespond to the numbers listed in Table 1.

Example 1 Synthesis of Methyl 4-nitrophenyl Carbonate (12)

[0057] To an ice cold solution of 4-nitrophenol (7.36 g, 0.053 mol) andpyridine (4.3 g, 0.054 mol) in CH₂Cl₂ (80 mL) at 0-5° C. was added asolution of methylchloroformate(5 g, 0.053 mol) in CH₂Cl₂ (20 mL) andstirred for 15 min and then at room temperature overnight (16 h). Themixture was extracted with CH₂Cl₂ (50 mL), washed successively withwater (50 mL), aq. NaOH (0.5 N, 50 mL), sat. aq. NaCl solution (50 mL),water (3×50 mL) and dried (Na₂SO₄). The CH₂Cl₂ solution was passedthrough a silicagel column using chloroform (100%) as eluent to furnishpure carbonate 12 (10 g, 96%) as a white solid. Purification of thecarbonate by recrystallization gave 80% yield: TLC (R_(f)) 0.50 (100%CHCl₃); mp 111-112° C.; IR (KBr) 3121, 3086, 1766, 1618, 1602, 1522,1443, 1366, 938, 858, 667 cm⁻¹; ¹H NMR (CDCl₃) 8.24 (d, 2H, J=9.05 Hz,Ar—CH), 7.34 (d, 2H, J=9.05 Hz, Ar—CH), 3.91 (s, 3H, OCH₃); ¹³C NMR(CDCl₃), 155.71 (OCOO), 153.28 (Ar—OCO), 145.61 (C—NO₂), 125.51 (Ar—CH),121.96 (Ar—CH),56.07 (OCH₃); MS m/e (EI⁺, relative intensity, %) 197(25),153 (33), 123 (100), 95 (21), 92 (45), 77 (46), 64 (32), 63 (33),59 (55).

Example 2 2,5-Bis[4-(N-methoxycarbonyl)amidinophenyl]furan (2)

[0058] To a stirring suspension of bis-amidine 1 (0.5 g, 0.00164 mol) indry DMF (8 mL) at room temperature, was added a solution of methyl4-nitrophenyl carbonate (0.72 g, 0.0036 mol) in DMF (2mL) and themixture was stirred overnight (16 h). Water (20 mL) was added to themixture, stirred for few min and filtered, washed with water (2×10 mL),and ether (10 mL) and dried. Crystallization from ethanol gave purecarbamate 2 (80%) as a white solid: TLC (R_(f)) 0.49 (CHCl₃, MeOH,NH₄OH, 4:1:0.2, v/v); mp >300° C. dec.; IR (KBr) 3500-3100, 3010, 2956,1672, 1609, 1566, 1518, 1476, 1442, 1266, 1198, 1147, 1124, 1086, 1030,940, 856, 806, 786, 764, 674, 604, 548 cm⁻¹; ¹H NMR (DMSO-d₆) δ 9.11 (s,4H, NH), 8.07 (d, 2H, J=8.18 Hz, Ar—CH), 7.95 (d, 2H, J=8.30 Hz, Ar—CH),7.30 (s, 2H, furan—CH), 3.63 (s, NCOOCH₃); ¹³C NMR (DMSO-d₆) δ 165.61,164.36, 152.61, 132.96, 132.81, 128.36, 123.34, 110.52, 51.85 MS m/z(FAB, thioglycerol) 421 (M+1), 389, 363, 346, 321, 305, 289, 271, 257,237, 230. Anal. (C₂₂H₂₀N₄O₅) C,H,N.

Example 3 Synthesis of 4-nitrophenyl-2,2,2-trichloroethyl Carbonate (14)

[0059] To an ice cold solution of 4-nitrophenol (2.0 g, 14.4 mmol) andtriethylamine (1.6 g, 15.8 mmol) (or pyridine) in CH₂Cl₂ (20 mL) at 0-5°C. was added a solution of 2,2,2-trichloroethylchloroformate (3.2 g,1mmol) in CH₂Cl₂ (10 mL) and stirred for 15 min. and then at roomtemperature overnight (16 h). Aqueous work up as described above andpurification of the product by silicagel column chromatography usingchloroform (100%) as eluent furnished pure carbonate 14 (4.3 g 91%).Alternatively, the product is purified by recrystallization from hexanein 60% yield: TLC (R_(f)) 0.56 (100% CHCl₃); mp 59-60° C., IR (KBr)3123, 3093, 3012, 2967, 2871, 2462, 2365, 2343, 1771, 1630, 1541, 1496,1432, 1362, 1288, 1251, 1020, 954, 843, 783 cm⁻¹; ¹H NMR (CDCl₃) δ 8.33(d, 2H, J=9.36 Hz, Ar—CH), 7.45 (d, 2H, J=9.36 Hz, Ar—CH), 4.91 (s, 2H,OCH₂CCl₃), ¹³C NMR (CDCl₃) δ 155.21 (OCOO), 151.68 (Ar—OCO), 145.91(C—NO₂), 125.64, 121.89, 93.95 (CCl₃), 77.56 (CH₂CCl₃); MS m/e (EI⁺,relative intensity, %) 314 (M⁺, 1), 313 (5), 280 (17), 278 (26), 196(14), 182 (25), 166 (74), 139 (100), 135 (20), 133 (57), 131 (58), 122(24), 109 (40), 95 (32), 63 (22). Anal. (C₉H₆NO₅Cl₃) C,H.

Example 4 Synthesis of2,5-bis[4-(N-2,2,2-trichloroethoxycarbonyl)amidinophenyl]furan (3)

[0060] To a suspension of amidine 1 (0.5 g, 0.00164 mol) anddiisopropylethylamine (0.43 g, 0.0033 mol) in THF/CH₃CN mixture (20 mL,1:1 v/v) at room temperature, was added a solution of4-nitrophenyl-2,2,2-trichloroethyl carbonate (1.1 g, 0.0035 mol) in THF(10 mL) and stirred for 24 h. The solvents were removed in a rotavap andthe residue was cooled in ice, triturated with anhydrous diethyl ether(20 mL), filtered, washed with ether (2×20 mL), dried and crystallizedfrom CHCl₃-ether mixture to obtain 2,2,2-trichloroethylcarbamate (3)(0.65 g, 60% yield) as a yellow solid: TLC (R_(f)) 0.6; (CHCl₃, MeOH,NH₄OH, 4:1:0.2, v/v); mp 134-136CO; IR (KBr) 3509-3029, 3010, 2997,2952, 1682, 1615, 1600, 1517, 1492, 1485, 1412, 1377, 1251, 1147, 1130,1120, 1058, 1028, 939, 849, 798, 730, 716, 634, 560 cm⁻¹; ¹H NMR(DMSO-d₆) δ 9.80-9.60 (br s, 4H, NH), 8.07 (d, J=8,.73 Hz, 4H, Ar—CH),8.02 (d, J=8.73 Hz, 4H, Ar—OH), 7,39 (s, 2H, CH—furan), 4.98 (s, 4H,OCH₂CCl₃); ¹³C NMR (DMSO-d₆) δ 166.35, 152.58, 133.57, 129.23, 123.39,111.23, 95.57 (CCl₃), 74.49 (CH₂CCO₃); MS m/z (FAB, thioglycerol): 656(M+1, 9 isotopic peaks), 507 (7 peaks), 481 (8 peaks), 481 (8 peaks),464.0 (6 peaks), 357 (3 peaks), 314 (3 peaks), 304, 288, 271, 262, 245,232. Anal. (C₂₄H₁₈N₄O₅Cl₆) C, H, N.

Example 5 Synthesis of 4-nitrophenyl Thioethyl Carbonate (18)

[0061] Thiocarbonate 18 was synthesized from 4-nitrophenol andthioethylchloroformate in pyridine/CH₂Cl₂ as described previously, in92% yield and subsequently purified by silica column chromatography toafford pure colorless crystals: TLC (R_(f)) 0.6 (100% CHCl₃); mp 65-66°C.; IR (KBr) 3120, 3089, 2944, 2588, 2000, 1942, 1740, 1528, 1454, 1352,1198, 1102, 894, 748, 660, 526 cm⁻¹; ¹H NMR (CDCl₃) d 8.25 (dd, 2H,J=4.92, 2.07 Hz, Ar—CH), 7.33 (dd, 2H, J=4.92, 2.22 Hz, Ar—CH), 2.96 (q,2H, J=14.84 Hz, SCH₂), 1.38 (t, 3H, J=7.46 Hz, CH₃; ¹³C NMR (CDCl₃) d169.70, 155.79, 145.52, 125.44, 122.21, 26.04 (SCH₂), 14.85 (CH₃); MSm/e (EI⁺, relative intensity, %) 227 (M⁺, 4), 139 (12), 109 (19), 89(100), 63 (12). Anal. (C₉H₉NO₄S) C,H.

Example 6 Synthesis of2,5-bis[4-(N-thioethylcarbonyl)amidinophenyl]furan (4)

[0062] To a suspension of bis-amidine 1 (0.6 g, 0.002 mol) in DMF (10mL) at room temperature, was added a solution of 4-nitrophenylethylthiocarbonate (0.9 g, 0.004 mol). The resulting solution wasstirred for 24 h. Ice water (40 mL) was added to the mixture andfiltered, washed with water (3×30 mL), ether (30 mL) and dried. Thecrude solid was purified by crystallization from ethanol-ether tofurnish carbamate 4 (0.6 g, 62%) as a yellow solid: TLC (R_(f)) 0.58(CHCl₃ MeOH, NH₄OH, 4:1:0.2, v/v); mp>3000; IR (KBr) 3442-3200, 3040,2970, 2928, 2866, 1668, 1610, 1592, 1562, 1469, 1413, 1382, 1320, 1305,1283, 1208, 1130, 1110, 1090, 1016, 939, 885, 842, 768 cm⁻¹; ¹H NMR(DMSO-d₆) δ 9.26 (d, 4H, D₂O exchangeable, J=45 Hz, NH), 8.07 (d, 4H,J=8.42 Hz, Ar—CH), 7.96 (d, 4H, J=8.30 Hz, Ar—CH), 7.31 (s, 2H,CH—furan), 2.78 (q, 4H, J=14.3 Hz, SCH₂), 1.24 (t, 6H, J=7.32 Hz,SCH₂CH₃); ¹³C NMR (DMSO-d₆) δ 181.37, 162.06, 152.64, 132.95, 132.35,128.70, 123.43, 110.76, 24.06 (SCH₂), 15,34 (SCH₂CH₃); MS m/z (FAB,m-nitrobenzoic acid) 481 (M+1), 429, 413, 397, 321, 298, 272, 257, 231.Anal. (C₂₄H₂₄N₄O₃S₂.0.25H₂O) C, H, N.

Example 7 Benzyl-4-nitrophenylcarbonate (19)

[0063] Carbonate 19 was synthesized from 4-nitrophenol andbenzylchloroformate as described above, in 80% yield after silica columnpurification, as a white solid: TLC (R_(f)) 0.55 (100% CHCl₃); mp 81°C.; IR (KBr) 3098, 3034, 2855, 1758, 1617, 1528,1387, 1355, 1285, 1227,1112, 1049, 965, 870, 780, 729, 583, 511 cm⁻¹; ¹H NMR (CDCl₃) d 8.26 (d,2H, J=9.4 Hz), 7.43 (m, 5H, Ar—CH of benzyl), 7,37 (d, 2H, J=9.4 Hz,OCH₂—Ar); ¹³C NMR (CDCl₃): δ 155.53, 152.45, 145.40, 134.20, 129.07,128.81, 128.66, 125.30, 121.77, 71.01; MS m/e (EI⁺, relative intensity,%) 274, 244, 230, 199, 140, 131, 108.

Example 8 Synthesis of2,5-bis[4-(N-benzyloxycarbonyl)amidinophenyl]furan (5) and DimaleateSalt

[0064] To a suspension of bis-amidine 1 (0.5 g, 0.0016 mol) in DMF (10mL) at room temperature, was added benzyl-4-nitrophenylcarbonate (1.6 g,0.006 mol). The resulting solution was stirred for 24 h and ice water(40 mL) was then added and extracted with CHCl₃ (2×50 mL). The CHCl,extract was washed with aq. NaOH (1 N, 40 mL), sat. NaCl (40 mL), water(50 mL) and dried (Na₂SO₄). The solution was filtered, concentrated in arotavap, cooled in ice bath, triturated with ether (30 mL), filtered,washed with ether (3×20 mL) and dried under vacuum for 16 h to affordcarbamate 5 as a shiny pale yellow solid (0.77 g, 52%): TLC (R_(f)) 0.76(CHCl₃, MeOH, NH₄OH, 4:1:0.2, v/v); mp 225° C. dec.; IR (KBr) 3480-3140,3111, 3087, 3063, 3032, 2960, 2866, 1667, 1612, 1570, 1507, 1497, 1375,1296, 1266, 1145, 926, 859, 787, 744, 702 cm⁻¹; ¹H NMR (DMSO-d₆) δ 9.16(s, 4H, D₂O exchangeable, NH), 8.09 (d, 4H, J=8.57 Hz, Ar—CH), 7.95 (d,4H, J=8.57 Hz, Ar—CH), 7.42-7.31 (2×d+3×t, 10, Ar—CH), 7.30 (s, 2H,CH—furan), 5.13 (s, OCH₂Ph, 4H ¹³C NMR (DMSO-d₆) δ 165.97, 163.69,152.62, 137.12, 132.89, 132.86, 128.44, 128.35, 127.97, 127.77, 123.35,110.60, 66.04 (OCH₂Ph); MS m/e (FAB, m-nitrobenzoic acid) 573 (M+1),460, 439, 421, 378. Anal. (C₃₄H₂₈N₄O₅.2H₂O) C, H, N.

[0065] A mixture of the carbamate free base 5 (0.49, 0.0007 mol), maleicacid (0.18 g, 0.0016 mol) and dry ethanol (20 mL) was stirred at roomtemperature for 4 h. The mixture was cooled in ice bath, triturated withdry Et₂O (25 mL), filtered, washed with Et₂O (3×10 mL) and dried in avacuum oven at 50° C. overnight to afford 5-dimaleate salt as a yellowsolid (0.53 g, 94%): mp 155-157° C. dec.; IR (KBr); 3480-3140, 3111,3087, 3063, 3032, 2960, 1667, 1612, 1570, 1507, 1497,1375, 1266, 1145,926, 859, 787, 744, 702 cm⁻¹; ¹H NMR (DMSO-d₆) δ 9.40-9.80 (br s, 2H,D₂O exchangeable, NH), 8.03 (d, 4H, J=8.56 Hz, Ar—CH), 7.99 (d, 4H,J=8.56 Hz, Ar—CH), 7.42-7.31 (2×d+3×t, 10H, Ar—CH), 7.35 (s, 2H,CH—furan), 6.18 (s, 2H, O₂CCH═CHCO₂), 4.19 (s, 4H, OCH₂Ph); ¹³C NMR(DMSO-d₆) δ 166.77, 165.49, 152.57, 136.39, 133.34, 132.07, 128.94,128.39, 128.11, 128.01, 123.36, 111.03, 66.72 (OCH₂Ph); MS m/e (FAB,m-nitrobenzoic acid) (free base) 573.2, 460.1, 421.2, 378.2; Anal.(C₄₂H₃₆N₄O₁₃) C, H, N.

Example 9 Synthesis of 4-bromomethyl-5-methyl-1,3-dioxol-2-one

[0066] A mixture of 4,5-dimethyl-1,3-dioxol-2-one (15.0 g, 0.132 mol),a,a-azobisisobutyronitrile (AIBN) (1.08 g, 0.0066 mol) andN-bromosuccinimide (23.4 g, 0.132 mol) in freshly distilled carbontetrachloride (350 mL) was refluxed under nitrogen for 16 h. The mixturewas concentrated to one-half the initial volume, cooled in an ice bathand the white solid was filtered off. Concentration of the filtrate(CCl₄ solution) in a rotavap under reduced pressure gave4-bromomethyl-5-methyl-1,3-dioxol-2-one as a pale brown liquid in 90%yield (25 g). Due to the instability of the product at room temperature,it was used without purification for the next step. However, a smallamount of the crude produce (100 mg) was purified for NMR analysis,through a short pad of silicagel using CHCl, (100%) as eluent. ¹H NMR(CDCl₃) δ 4.21 (s, 2H, CH₂Br), 2.14 (s, 3H, CH₃); ¹³C NMR (CDCl₃) δ151.72 (OCOO, 138.08 (═CCH₂Br), 134.62 (═C—CH₃), 18.01 (CH₂Br), 9.51(CH₃).

Example 10 Synthesis of (5-methyl-1,3-dioxol-2-one-4-yl)methyl Formate

[0067] To an ice cold solution of4-bromomethyl-5-methyl-1,3-dioxol-2-one (24 g, 0.124 mol) and formicacid (19.5 g, 0.43 mol) in acetonitrile (250 mL) at 0° C. was addedtriethylamine (44 g, 0.44 mol) dropwise over a period of 15 min. Icebath was then removed and the mixture was stirred at room temperaturefor 2 h. The mixture was concentrated to one-half the initial volume ona rotavap and extracted with ethyl acetate (2×150 mL). The organicextract was washed successively with satd. NaHCO₃ (200 mL), satd. NaCl(200 mL), water (200 mL) and dried (Na₂SO₄). Concentration of thefiltrate gave crude formate ester as a colorless liquid (20 g): ¹H NMR(CDCl₃) δ 8.06 (s, 1H, CH₂OOCH), 4.91 (s, 2H, CH₂), 2.16 (s, CH₃); ¹³CNMR (CDCl₃) δ 160.26 (CH₂OOCH), 152.06 (OCOO), 140.59 (═CCH₂), 133.14(═C—CH₃), 53.15 (CH₂OOCH), 9.42 (CH₃).

Example 11 Synthesis of 4-Hydroxymethyl-5-methyl-1,3-dioxol-2-one

[0068] To a solution of the crude formate (19.9 g) and 80% methanol (250mL) at room temperature was added conc. HCl (1 mL) and stirred for 6 h.Methanol was evaporated off in rotavap at 30° C. under reduced pressureand the residue was extracted with ethyl acetate. Passage through ashort pad of silica gel and concentration gave4-hydroxymethyl-5-methyl-1,3-dioxol-2-one as a colorless oil (7.0 g,43%), ¹H NMR (CDCl₃) δ 4.37 (s, 2H, CH₂OH), 2.80 (s, 1H, OH, D₂Oexchangeable), 2.11 (s, 3H, CH₃); ¹³C NMR (CDCl₃) δ 152.94 (OCOO),137.63 (═CCH2OH), 135.01 (═CCH₃), 53.32 (CH₂OH), 9.33 (CH₃).

Example 12 Synthesis of4-methyl-2-oxo-1,3-dioxiol-4-en-5-yl)methyl-4-nitrophenyl Carbonate (23)

[0069] Carbonate 23 was synthesized from4-methyl-5-hydroxymethyl-1,3-dioxol-4-ene-2-one and4-nitrophenylchloroformate in CH₂Cl₂/pyridine and purified bycrystallization from chloroform colorless crystals in 76% yield: TLC(R_(f)) 0.23 (100% CHCl₃); mp 120-121° C. (lit.³¹ 116-117° C.); IR (KBr)3115, 3096, 2928, 2854, 1811, 1780, 1742, 1619, 1593, 1525, 1494, 1352,1308, 1246, 1221, 1054, 860, 768 cm⁻¹; ¹H NMR (CDCl₃) δ 8.29 (d, 2H,J=9.04 Hz), 7.39 (d, 2H, J=9.20 Hz), 5.03 (s, 3H, C═CCH₃), 2.22 (s, 2H,OCOOCH₂); ¹³C NMR (CDCl₃) δ 155.36 (OC═OO), 152.46, 151.85 (vinyleneC═O), 145.93 (Ar—NO₂), 141.62, 132.45, 125.59, 121.90, 58.37 (OCH₂),9.65 (C═CCH₃); MS m/e (EI⁺, relative intensity, %) 295 (M⁺, 1), 139 (9),113 (100), 69 (23), 43 (74). Anal. (C₁₂H₉NO₈) C, H, N.

Example 13 Synthesis of2,5-bis{4-[N-(5-methyl-2-oxo-1,3-dioxol-4-ene-1-yl)methoxycarbonyl]amidinophenyl}furan (6)

[0070] To a suspension of bis-amidine 1 (0.7 g, 0.0023 mol) in DMF (15mL) at room temperature, was added a solution of(4-methyl-2-oxo-1,3-dioxol-4-ene-1-yl) methyl 4-nitrophenyl carbonate(1.5 g, 0.0052 mol) in DMF (5 mL) and stirred for 24 h. Ice water (50mL) was added, filtered, washed with water (3×20 mL), ether (30 mL) anddried under vacuum. The crude product was crystallized from CHCl₃-ethermixture to yield pure 6 (1.26 g. 89%) as a yellow solid: TLC (R_(f))0.33 (CHCl₃ MeOH, NH₄OH, 4:1:0.2, v/v); mp 153-155° C.; IR (KBr)3500-3120, 3105, 3075, 2866, 3037, 1825, 1667, 1660, 1618, 1610, 1521,1497, 1417, 1394, 1266, 1230, 1145, 1094, 989, 927, 787, 687 cm⁻¹; ¹HNMR (DMSO-d₆) δ 9.19 (s, 4H, D₂O exchangeable, NH), 8.09 (d, J=8.43 Hz,Ar—CH), 7.96 (d, 4H, J=8.24 Hz, Ar—CH), 7.31 (s, 2H, CH—furan), 4.95 (s,4H, OCH₂), 2.18 (s, 6H, C═CCH₃); 130 NMR (DMSO-d₆) δ 166.23, 162.91,152.60 (C═O, dioxolone), 151.96, 139.53, 134.09, 132.96, 132.65, 128.47,123.35, 110.66, 54.17 (OCH₂), 8.82 (C═CCH₃); MS m/z (FAB, m-nitrobenzoicacid) 617 (M+1), 505, 487, 460, 443, 424, 375, 357. Anal. (C₃₃H₂₄N₄O₁₁)C, H, N.

Example 14 Synthesis of Diphenyl Carbonate (20)

[0071] Carbonate 20 was prepared by reaction of phenol withphenylchloroformate in pyridine/CH₂Cl₂ followed by aqueous workup asdescribed above in 90% yield as a white solid: TLC (R_(f)) 0.7 (100%CHCl₃); mp 79-80° C.; IR (KBr) 3066, 1776, 1604, 1495, 1457, 1400, 1285,1189, 997, 755, 691 cm⁻¹; ¹H NMR (CDCl₃) δ 7.40 (t, 4H, J=8.02 Hz), 7.26(d, 6H, J=8.73 Hz); ¹³C NMR (CDCl₃) δ 152.29, 151.14, 129.77, 126.50,121.10; MS m/e (EI⁺, relative intensity, %) 214 (M⁺, 100), 170 (46), 169(37), 142 (43), 141 (64), 94 (13), 77 (87), 65 (26), 51 (25), 39 (23).

Example 15 Synthesis of 2,5-Bis[4-(N-phenoxycarbonyl)amidinophenyl]furan(7)

[0072] To a suspension of bis-amidine 1 (0.5 g, 0.0016 mol) in DMF (10mL) at room temperature, was added diphenylcarbonate (0.77 g, 0.0036mol). The resulting solution was stirred for 24 h and ice water (40 mL)was then added and the resulting solid was filtered, washed with plentyof water (3×30 mL), ether (2×30 mL) and dried under vacuum in adessicator for 16 h to furnish carbamate 7 (0.53 g, 63%) as a yellowsolid: TLC (R_(f)) 0.68 (CHCl₃, MeOH, NH₄OH, 4:1:0.2, v/v); mp>300° C.;IR (KBr) 3680-3000, 1674, 1615, 1462, 1515, 1488, 1412, 1382, 1266,1199, 1170, 1145, 1030, 1016, 939, 969, 864, 798, 738, 693, 589 cm⁻¹; ¹HNMR (DMSO-d₆) δ 9.30 (s, 4H, D₂O exchangeable, NH), 8.12 (d, 4H, J=7.61Hz, Ar—CH), 7.98 (d, 4H, J=7.30 Hz, Ar—CH), 7.44 (t, 4H, J=7.46 Hz,Ar—m-H), 7.33 (s, 2H, CH—furan), 7.22 (t, 2H, J=6.19 Hz, Ar—p-CH), 7.20(d, 4H, J=8.57 Hz, Ar—o-CH); ¹³ C NMR (DMSO-d₆) δ 166.78, 162.12,152.65, 151.63, 151.63, 133.08, 132.58, δ 129.17, 128.59, 124.92,123.43, 121.95, 115.19, 110.79; MS m/z (FAB, m-nitrobenzoic acid) 545(M+1), 460, 451, 425, 408, 391, 357, 329. Anal. (C₃₂H₂₄N₄O₅) C, H, N.

Example 16 Synthesis of bis(4-flourophenyl)carbonate (21)

[0073] Reaction of 4-fluorophenol with 4-fluorophenylchloroformate inpyridine/CH₂Cl₂ as described earlier afforded carbonate 21 after silicacolumn chromatography in 85% yield as a white solid: TLC (100% CHCO₃)0.7; mp 122-123° C.; IR (KBr) 3130, 3091, 1885, 1764, 1649, 1610, 1508,1304, 1234, 1176, 1094, 1010, 902, 838, 729, 576, 510 cm⁻¹; ¹H NMR(CDCl₃) δ 7.24 (dd, 4H, J=9.05, 4.44 Hz), 7.08 (dd, 4H, J=8.89, 8.09Hz); ¹³C NMR (CDCl₃) δ 161.93, 159.50, 152.34, 147.06, 147.03, 122.61,122.53, 116.60, 116.36; MS m/e (EI⁺, relative intensity, %) 250 (M⁺, 82)206 (27), 178 (12), 177 (43), 139 (11), 112 (25), 111 (20), 95 (100), 83(32), 75 (19), 57 (17).

Example 17 Synthesis of2,5-bis[4-(N-(4-fluoro)phenoxycarbonyl)amidinophenyl]furan (8)

[0074] To a suspension of bis-amidine 1 (0.5 g, 0.0026 mol) in DMF (10mL) at room temperature, was added a solution of carbonate 21 (0.87 g,0.0035 mol). The resulting solution was stirred for 16 h. Ice water (40mL) was added to the mixture and filtered, washed with water (3×30 mL),ether (30 mL) and dried in vacuum for 24 h to furnish4-fluorophenylcarbanate 8 (0.92 g, 61%) as a yellow solid: TLC (R_(f))0.45 (CHCl₃, MeOH, NH₄OH, 4:1:0.2, v/v); mp>300° C.; IR (KBr) 3465-3000,1667, 1621, 1491, 1260, 1187, 1139, 1078, 969, 859, 793, 665 cm⁻¹; ¹HNMR (DMSO-d₆) δ 9.31 (s, 4H, D₂O exchangeable, NH), 8.12 (d, J=8.73 Hz,Ar—CH), 7.98 (d, 4H, J=8.57 Hz, Ar—CH), 7.33 (s, 2H, CH—furan), 7.22 (d,8H, J=6.5 Hz, F—Ar—CH) ¹³C NMR (DMSO-d₆) δ 162.12, 161.86, 157.77,156.53, 154.21, 153.45, 152.57, 147.76, 133.00, 132.45, 132.65, 128.79,128.44, 127.83, 123.46, 123.38, 123.31, 115.97, 115.89, 115.60, 115.47,115.37, 115.25; MS m/z (FAB, m-nitrobenzoic acid) 581 (M+1), 469, 443,426, 357, 331. Anal. (C₃₂H₂₂N₄O₅F₂.0.5H₂O) C, H, N.

Example 18 Synthesis of bis(4-methoxyphenyl)carbonate (22)

[0075] Reaction of 4-methoxyphenol with 4-methoxyphenylchloroformate inpyridine/CH₂Cl₂ followed by aqueous workup as described above gavecarbonate 22, after silica column chromatography, in 93% yield as awhite solid: TLC (R_(f)) 0.53 (100% CHCl₃); mp 95° C.; IR (KBr) 3076,2958, 2848, 1772, 1610, 1514, 1470, 1286, 1242, 1182, 1028, 894, 836,776, 726, 534 cm⁻¹; ¹H NMR (CDCl₃) δ 7.16 (d, 4H, J=9.05 Hz), 6.88(d,4H, J=9.04Hz), ¹³C NMR (CDCl₃) δ 157.71, 153.04, 144.83, 121.96, 114.68,55.80 (OCH₃); MS m/e (EI⁺, relative intensity, %) 274 (M⁺, 100), 230(33), 215 (29), 187 (12), 124 (16), 123 (46), 107 (10), 95 (12), 77(13), 64 (7), 52 (5), 41 (6).

Example 19 Synthesis of 2,5-bis[4-(N-(4-methoxy)phenoxycarbonyl)amidinophenyl]furan (9)

[0076] To a suspension of bis-amidine 1 (0.7 g, 0.0016 mol) in DMF (10mL) at room temperature, was added bis(4-methoxy)phenylcarbonate (1.39g, 0.0051 mol) and stirred for 24 h. Anhydrous ether (25 mL) was thenadded to the precipitated product, stirred for few min and filtered,washed with ether (3×15 mL) and dried under vacuum in a dessicator for48 h to furnish 4-methoxyphenyl carbamate 9 (0.9 g, 65%) as a yellowsolid: TLC (R_(f)) 0.68 (CHCl₃,MeOH, NH₄OH, 4:1:0.2, v/v); mp>300° C.;IR (KBr) 3450-3100, 3010, 2934, 2836, 1683, 1484, 1256, 1184, 1142,1078, 1033, 1010, 967, 928, 850, 801, 774, 753, 696, 659, 607, 583, 559,531 cm⁻¹; ¹H NMR (DMSO-d₆) δ 9.26 (s, 4H, NH), 8.11 (d, 4H, J=8.54 Hz,Ar—CH), 7.98 (d, 4H, J=8.53 Hz, Ar—CH), 7.34 (s, 2H, furan—CH), 7.09 (d,4H, J=9.04 Hz, Ar—CH of Ar—OCH₃), 6.93 (d, 4H, J=9.03 Hz, Ar—CH ofAr—OCH₃), 3.75 (s, 6H, OCH₃); ¹³C NMR (DMSO-d₆) δ 166.62, 156.26,152.64, 145.07, 133.03, 132.64, 128.53, 123.41, 122.66, 114.12, 110.72,55.36. MS m/z (FAB, thioglycerol) 605 (M+1), 481, 429, 323, 303, 289,273, 257, 247, 229. Anal. (C₃₄H₂₈N₄O₇.1.DMF) C, H, N.

Example 20 Synthesis of 1-chloroethyl-4-nitrophenylcarbonate (16)

[0077] To an ice cold solution of 4-nitrophenol (2.0 g, 0.015 mol) andtriethylamine (1.6 g, 0.016 mol) (or pyridine) in CH₂Cl₂ (20 mL) at 0-5°C. was added a solution of 1-chloroethylchloroformate (2.1 g, mmol) inCH₂Cl₂ (10 mL) and stirred for 15 min and then at room temperatureovernight (16 h). The mixture was extracted with CH₂Cl₂ (50 mL), aq.NaOH (0.5 N, 50 mL), sat. NaCl solution (50 mL), water (3×50 mL) anddried (Na₂SO₄). The CH₂Cl₂ solution was filtered, evaporated in arotavap and the residue was purified by silicagel column chromatographyusing chloroform (100%) as eluent to furnish pure 16 as a white solid:TLC (R_(f)) 0.75 (CHCl₃); mp 70-71° C. (lit.²² 69-70° C.); IR (KBr)3116, 3084, 2999, 2932, 2864, 2364, 2330, 1779, 1626, 1525, 1355, 1245,1101, 914, 863, 779, 677 cm⁻¹; ¹H NMR (CDCl₃) δ 8.31 (dd, 2H, J=5.08,2.07 Hz, Ar—CH), 7.43 (dd, 2H, J=4.76, 2.22 Hz, Ar—CH), 6.50 (q, 1H,J=11.67 Hz, CHClCH₃), 1.93 (d, 3H, J=5.87 Hz); ¹³C NMR (CDCl₃) δ 155.16,150.65, 145.94, 125.63, 121.89, 85.44, 25.34; MS m/e (EI⁺, relativeintensity) 210 (M⁺—HCl, 4), 139 (26), 122 (13),109 (8), 76 (13), 75(11), 65 (27), 64 (17), 63 (100), 50 (10), 43 (13).

Example 21 Synthesis of 1-acetoxyethyl-4-nitrophenylcarbonate (17)

[0078] To a solution of 1-chloroethyl-4-nitrophenyl carbonate (2.0 g,0.0082 mol) in glacial acetic acid (50 mL) at room temperature, wasadded mercuric acetate (3.8 g, 0.012 m) and the mixture was stirred for40 h. Water (100 mL) was then added to the mixture and extracted withether (2×75 mL). The ethereal phase was washed with aq. NaOH (0.5 N, 30mL), sat. NaCl (30 mL), water (2×50 mL) and dried (anhy. Na₂SO₄). Thesolution was filtered, concentrated in a rotavap and purified by silicagel column chromatography to afford pure 1-acetoxyethyl-4-nitrophenylcarbonate (17) (1.9 g, 89%) as a colorless liquid: TLC (R_(f)) 0.65(CHCl₃); IR (film) 1779 (OCOO), 1749 (CH₃COO), 1615, 1592, 1528, 1491,1266, 1110, 1070, 857 cm⁻¹; ¹H NMR (CDCl₃) δ 8.29 (d, 2H, J=9.05 Hz,Ar—CH), 7.41 (d, 2H, J=9.04 Hz, Ar—CH), 6.84 (q, 1H, J=10.95 Hz,CH(Oac)CH₃), 2.14 (s, 3H, COCH₃), 1.62 (d, 3H, 5.4 Hz, CHCH₃); ¹³C NMR(CDCl₃) δ 169.09, 155.33, 150.70, 145.76, 125.52, 121.94, 92.47 (CHOAc),20.96 (COCH₃), 19.61 (CHCH₃), MS m/e (EI⁺, relative intensity) 210(M⁺—AcOH, 3), 166 (4), 122 (5), 87 (33), 63 (6), 50 (3), 43 (100).

Example 22 Synthesis of2,5-bis[4(1-acetoxyethoxycarbonyl)amidinophenyl]Furan (10)

[0079] A mixture of bis-amidine 1 (0.4 g, 0.0013 mol),diisopropylethylamine (0.35 g, 0.0026 mol) and THF/CH₃CN (1:1 mixture,15 mL) was stirred at room temperature. A solution of1-aceoxyethyl-4-nitrophenyl carbonate (0.71 g, 0.00264 mol) in THF (5mL) was then added and continued stirring for 24 h. Solvents wereremoved in a rotavap under reduced pressure at 40° C., triturated withanhy. ether (20 mL), filtered, washed with ether (2×25 mL), dried in airand crystallized from CHCl₃ether to yield 1-acetoxyethyl carbamate (10)as a yellow solid in 71% yield (0.52 g): TLC (R_(f)) 0.5(CHCl₃,MeOH,NH₄OH, 4:1:0.2, v/v); mp 165-167° C. dec; IR (KBr) 3690-2900(br), 3458 (s), 3324 (s), 3131 (s), 2945 (s), 1734, 1667, 1640, 1607,1562, 1488, 1412, 1362, 1279, 1243, 1147, 1117, 1089, 1057, 1022, 992,932, 885, 842, 797, 597, 566 cm⁻¹; ¹H NMR (DMSO-d₆) δ 9.33 (s, 4H, NH),8.09 (d, 4H, J=8.54 Hz, Ar—CH), 7.96 (d, 4H, J=8.54 Hz, Ar—CH), 7.34 (s,2H, CH—furan), 6.79 (q, 2H, J=10.87 Hz, CHOAc), 2.03 (s, 6H, CH,), 1.55(d, 6H, J=5.39 Hz, CHCH₃); ¹³C NMR (DMSO-d₆) δ 168.93, 166.84, 161.49,152.65, 133.06, 132.58, 128.59, 123.42, 110.82, 89.18, 20.82, 19.63(CH₃); MS m/z (FAB, thioglycerol) 565 (M+1), 479, 461, 435, 375, 357,331, 314, 288, 271. Anal. (C₂₈H₂₈N₄O) C, H, N.

Example 23 Synthesis of2,5-bis[4(N-ethoxycarbonyloxy)amidinophenyl]furan (11): NaOH Method

[0080] To a suspension of the bis-amidoxime(2,5-bis[4-(N-hydroxy)amidino phenyl]furan) (0.86 g, 0.0028 mol) andCH₂Cl₂ (15 mL), a solution of ethylchloroformate (1.22 g, 0.011 mol) inCH₂Cl₂ (15 mL) was added and stirred for 10 min. Aq. NaOH (1 N, 12 mL)was then added dropwise and stirred at room temperature for 6 h. Icewater (10 mL) was added, filtered, washed with plenty of water (3×30mL), dried in air and crystallized from ethanol to give pure ethylcarbonate (11) (0.67 g, 50% yield) as a white solid.

Example 24 Synthesis of Ethyl 4-nitrophenylcarbonate (13):CarbonateMethod

[0081] Reaction of 4-nitrophenol with ethylchloroformate inpyridine/CH₂Cl₂ as described earlier, gave carbonate 2 as colorlesscrystals in 92% yield by chromatographic purification and 82% bycrystallization methods. TLC (R_(f)) 0.48 (100% CHCl₃); mp 70-71° C.; IR(KBr) 3124, 3092, 3010, 2920, 2866, 1772, 1622, 1600, 1536, 1278, 1112,1060, 1006, 908, 860, 774, 732, 662, 527, 502 cm⁻¹; ¹H NMR (CDCl₃) δ8.29 (d, 2H, J=9.05 Hz, Ar—CH), 7.38 (d, 2H, J=9.05 Hz, Ar—OH), 4.36 (q,2H, OCH₂, J=14.28 Hz), 1.38 (t, 3H, J=7.07 Hz, CH₃): ¹³C NMR (CDCl₃) δ155.84, 152.65, 145.64, 125.48, 121.98, 65.74, 14.35; MS m/e (EI⁺,relative intensity, %) 212 (M⁺, 1.4), 211 (1), 139 (100), 109 (60), 89(100), 93 (13), 81 (11), 65 (21), 63 (13).

[0082] Reaction of bis-amidoxime with ethyl 4-nitrophenyl carbonate inDMF at room temperature gave bis-ethoxycarbonyloxy derivative in 85%yield as a white solid. The physical data for compound 11 obtained byboth methods were virtually identical. TLC (R_(f)) 0.5(CHCl₃,MeOH,NH₄OH, 4:1:0.2, v/v); mp>300° C. dec.; IR (KBr) 3700-3100,3056, 2989, 2937, 2915, 2890, 1770, 1668, 1635, 1481, 1414, 1370, 1266,1208, 1124, 1035, 1013, 939, 857, 834, 775, 686 cm⁻¹; ¹H NMR (DMSO-d₆) δ7.91 (d, 4H, J=7.21 Hz, Ar—CH), 7.78 (d, 4H, J=7.20 Hz, Ar—CH), 7.24 (s,2H, CH—furan), 6.89 (s, 4H, NH), 4.20 (q, 4H, J=14 Hz, NOCOOCH₂), 1.26(t, 6H, J=7.1 Hz, CH₃); ¹³C NMR (DMSO-d₆) δ 156.0 (OCOO), 153.48,152.43, 131.63, 130.17, 127.29, 123.33, 109.70, 63.56, (OCH₂), 14.20(OCH₂CH₃); MS m/z (FAB, thioglycerol) 481 (M+1), 429, 393, 377, 347,323, 305, 288, 271, 237. Anal. (C₂₄H₂₄N₄O₇) C, H, N.

[0083] In the specification, and examples there have been disclosedtypical preferred embodiments of the invention and, although specificterms are employed, they are used in a generic and descriptive senseonly and not for the purposes of limitation the scope of the inventionbeing set forth in the following claims. TABLE 1 In vivo Activity ofCarbamate and Carbonate Prodrugs of 2,5-Bis(4-amidinophenyl)furan vs.Pneumocystis carinii

Dosage¹ Cysts/g of lung^(a) Compound R (μmol/kg/day) (% of control)Toxicity^(a) Saline — 100.0^(b) ± 13.24 0 Pentamidine iv @ 22.0 3.06 ±0.90 ++  1 H iv @ 13.3 0.83 ± 0.36 0 Oral @ 39.8 44.52 ± 13.30 0  2^(c)

iv @ 22.0 Oral @ 33.0 6.91 ± 6.01 49.68 ± 20.50 0 0  3^(d)

iv @ 22.0 Oral @ 33.0 1.55 ± 1.79 8.59 ± 9.14 0 0  4

iv @ 22.0 Oral @ 33.0 83.01 ± 43.65 19.52 ± 14.22 0 0  5^(c)

iv @ 11.0 Oral @ 33.0 0.03 ± 0.02 18.09 ± 9.16 0 0  6^(d)

iv @ 22.0 Oral @ 33.0 0.02 ± 0.01 18.73 ± 11.87 0 0  7

iv @ 22.0 Oral @ 33.0 3.61 ± 1.80 5.70 ± 5.15 0 0  8^(d)

iv @ 22.0 Oral @ 33.0 0.02 ± 0.01 2.21 ± 0.33 0 0  9^(d)

iv @ 22.0 Oral @ 33.0 0.02 ± 0.01 2.10 ± 2.08 0 0 10^(c)

iv @ 11.0 Oral @ 33.0 1.21 ± 1.02 57.16 ± 10.19 ++0 11^(c)

iv @ 34.7 Oral @ 33.0 1.66 ± 0.58 96.90 ± 48.48 0 0

[0084] Calcd Calcd Calcd Found Found Found Compound for for for for forfor # Formula C H N C H N  2 C₂₀H₂₀N₄O₅ 62.84 4.80 13.33 63.01 4.7413.20  3 C₂₄H₁₈N₄O₅Cl₁₆ 41.70 3.20 8.11 41.54 3.01 8.28  4C₂₄H₁₄N₄O₃S₂.0.25H₂O 59.42 5.09 11.55 59.26 4.98 11.29  5C₃₄H₂₈N₄O₅.2H₂O 67.09 5.30 9.21 66.67 4.99 9.24  5M C₃₄H₂₈N₄O₅.2C₄H₄O₂62.68 4.51 6.96 62.71 4.47 7.04  6 C₃₀H₂₄N₄O₁₁ 58.44 3.92 9.09 58.404.00 9.09  7 C₃₂H₂₄N₄O₅.1.3H₂O 67.67 4.72 9.87 67.29 4.53 10.35  8C₃₂H₂₂N₄O₅F₃.0.5H₂O 65.12 4.10 9.51 64.82 4.20 10.03  9 C₃₄H₂₈N₄O₇.DMF65.57 5.21 10.33 67.44 5.19 10.17 10 C₂₈H₂₈N₄O₉ 59.57 5.00 9.93 59.415.06 9.82 11 C₂₄H₂₄N₄O₇ 60.00 5.04 11.66 59.67 4.95 11.46

That which is claimed:
 1. A method of treating an infection in a subjectin need of such treatment, said method comprising administering to saidsubject a compound of the formula (I):

wherein: X may be O, S, or NR′ wherein R′ is H or loweralkyl; R₁ and R₂may be independently selected from the group consisting of H,loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl, hydroxyalkyl,aminoalkyl, and alkylaminoalkyl; R₃ and R₄ are each independentlyselected from the group consisting of H, loweralkyl, halogen, oxyalkyl,oxyaryl, and oxyarylalkyl; R₅ is represented by a formula selected fromthe group consisting of:

 wherein: X₁, X₂, and X₃ are independently selected from O and S; and R₆and R₇are independently selected from the group consisting ofloweralkyl, aryl, alkylaryl, oxyaryl, an ester-containing substituent,and oxyalkyl; or a pharmaceutically acceptable salt thereof, and whereinsaid compound of Formula (I) is administered in an amount to treat theinfection.
 2. The method according to claim 1, wherein the infection isa microbial infection.
 3. The method according to claim 2, wherein themicrobial infection is Pneumocystis carinii pneumonia.
 4. The methodaccording to claim 1, wherein R₆ and R₇ are independently selected fromthe group consisting of: CH₃, CH₂CCl₃, CH₂CH₃,


5. The method according to claim 1, wherein each of the substituentspresent on the compound of formula (I) represented by the formula:

are present on the para positions of the aromatic groups on formula (I).6. The method according to claim 1, wherein said compound represented byformula (I) is administered to said subject orally or intravenously. 7.The method according to claim 1, wherein said compound represented byformula (I) is present in a pharmaceutical formulation and wherein saidpharmaceutical formulation further comprises a pharmaceuticallyacceptable carrier.
 8. The method according to claim 7, wherein R₆ andR₇ are independently selected from the group consisting of: CH₃,CH₂CCl₃, CH₂CH₃,


9. The method according to claim 7, wherein each of the substituentspresent on the compound of formula (I) represented by the formula:

are present on the para positions of the aromatic groups on formula (I).10. The method according to claim 7, wherein said compound representedby formula (I) is administered to said subject orally or intravenously.11. A compound for administering to a subject in need of treatmentrepresented by the formula (I):

wherein: X may be O, S, or NR′ wherein R′ is H or loweralkyl; R₁ and R₂may be independently selected from the group consisting of H,loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl, hydroxyalkyl,aminoalkyl, and alkylaminoalkyl; R₃ and R₄are each independentlyselected from the group consisting of H, loweralkyl, halogen, oxyalkyl,oxyaryl, and oxyarylalkyl; R₅ is represented by a formula selected fromthe group consisting of:

 wherein: X₁, X₂, and X₃ are independently selected from O and S; and R₆and R₇ are independently selected from the group consisting ofloweralkyl, aryl, alkylaryl, oxyaryl, an ester-containing substituent,and oxyalkyl; or a pharmaceutically acceptable salt thereof, and whereinsaid compound of Formula (I) is administered in an amount to treatPneumocystis carinii pneumonia.
 12. The compound according to claim 11,wherein R₆ and R₇ are independently selected from the group consistingof: CH₃, CH₂CCl₃, CH₂CH,


13. The compound according to claim 11, wherein each of the substituentspresent on the compound of formula (I) represented by the formula:

are present on the para positions of the aromatic groups on formula (I).14. A pharmaceutical composition comprising the compound as defined byclaim 11 and a pharmaceutically acceptable carrier.
 15. The compositionaccording to claim 14, wherein R₆ and R₇ are independently selected fromthe group consisting of: CH₃, CH₂CCl₃, CH₂CH₃,


16. The composition according to claim 14, wherein each of thesubstituents present on the compound of formula (I) represented by theformula:

are present on the para positions of the aromatic groups on formula (I).17. A process for making a pharmaceutically active bis-aryl carbamate,said process comprising: reacting an aryl carbonate with bis-amidine inthe presence of an organic solvent to form the bis-aryl carbamate. 18.The process according to claim 17, wherein the aryl carbonate isselected from the group consisting of diphenyl carbonate,bis(4-fluorophenyl)carbonate, bis(4-methoxyphenyl)carbonate,benzyl-4-nitrophenylcarbonate, 4-nitrophenyl thioethyl carbonate, and4-nitrophenyl-2,2,2-trichloroethyl carbonate, methyl 4-nitrophenylcarbonate, bis (3-fluorophenyl) carbonate, ethyl 4-nitrophenylcarbonate, (4-methyl-2-oxo-1,3-dioxol-4-en-5-yl)methyl 4-nitrophenylcarbonate, and I-acetoxyethyl 4-nitrophenyl carbonate.
 19. The processaccording to claim 17, wherein the pharmaceutically active bis-arylcarbamate is selected from the group consisting of2,5-bis[4-(N-2,2,2-trichloroethoxycarbonyl)amidinophenyl]furan,2,5-bis[4-(N-thioethylcarbonyl)amidinophenyl]furan,2,5-bis[4-(N-benzyloxycarbonyl)amidinophenyl]furan,2,5-bis[4-(N-phenoxycarbonyl)amidinophenyl]furan,2,5-bis[4-(N-(4-fluoro)phenoxycarbonyl)amidinophenyl]furan,2,5-bis[4-(N-(4-methoxy)phenoxycarbonyl)amidinophenyl]furan,2,5-bis[4(1-acetoxyethoxycarbonyl)amidinophenyl]furan, and 2,5-bis[4-(N-(3-thio)phenoxycarbonyl) amidinophenyl] furan.
 20. The processaccording to claim 17, wherein the pharmaceutically active bis-arylcarbamate may be represented by the formula:

wherein: X may be O, S, or NR′ wherein R′ is H or loweralkyl; R₁ and R₂may be independently selected from the group consisting of H,loweralkyl, oxyalkyl, alkoxyalkyl, cycloalkyl, aryl, hydroxyalkyl,aminoalkyl, and alkylaminoalkyl; R₃ and R₄ are each independentlyselected from the group consisting of H, loweralkyl, halogen, oxyalkyl,oxyaryl, and oxyarylalkyl; R₅ is represented by a formula selected fromthe group consisting of:

 wherein: X₁, X₂, and X₃ are independently selected from O and S; and R₆and R₇ are independently selected from the group consisting ofloweralkyl, aryl, alkylaryl, oxyaryl, an ester-containing substituent,and oxyalkyl.
 21. The process according to claim 20, wherein R₆ and R₇are independently selected from the group consisting of: CH₃, CH₂CCl₃,CH₂CH₃,


22. The process according to claim 20, wherein each of the substituentspresent on the compound of formula (I) represented by the formula:

are present on the para positions of the aromatic groups on formula (I).23. The process according to claim 17, wherein the aryl carbonate isrepresented by the formula:

wherein: R is represented by:

wherein X is selected from the group consisting of H, NO₂, F, and OCH₃;and wherein R′ is selected from the group consisting of CH₃, CH₃CH₂,CH₂CCl₃, CH(OAc)CH₂, CH₂C₆H₅, and

wherein X is selected from the group consisting of H, NO₂, F, and OCH₃.24. The process according to claim 23, wherein the aryl carbonate is asymmetrical aryl carbonate.
 25. The process according to claim 17,wherein the organic solvent is selected from the group consisting ofdimethyl formamide and tetrahydrofuran/CH₃CN.
 26. The process accordingto claim 25, wherein the tetrahydrofuran/CH₃CN is employed in thepresence of a base.
 27. The process according to claim 26, wherein thebase is diisopropylethylamine.